Anticoagulants are useful therapeutic agents in the pharmacological treatment of, for example, acute deep venous thrombosis, pulmonary embolism, acute arterial embolization of the extremities, myocardial infarction, stroke, restenosis and disseminated intravascular coagulation. Prophylactic administration of anticoagulants is believed to prevent a recurrence of embolism in patients with rheumatic or arteriosclerotic heart disease and to prevent certain thromboembolic complications of surgery. Administration of anticoagulants has also been indicated in the treatment of coronary artery and cerebrovascular disease. Arterial thrombosis, particularly in arteries supplying the heart muscle and brain, is a leading cause of death.
A current method for the treatment and prophylaxis of thrombotic diseases involves the inhibition of thrombin activity or thrombin formation, thus preventing clot formation. It is known in the art that the tripeptide (D)-Phe-Pro-Arg is a thrombin catalytic site inhibitor. Moreover, U.S. Pat. No. 5,391,705 describes polyfluorinated tripeptides which inhibit both thrombin and trypsin. Likewise, PCT Patent Application Publication No. WO 94/25051 describes thrombin inhibitors in which arginine is replaced with aminocyclohexyl moieties. However, the art does not appear to suggest that the tripeptide will retain antithrombin activity when tryptophan is substituted for arginine at the P.sub.1 position of the enzyme recognition site.
Applicants have discovered that when tryptophan is substituted for arginine or derivatives of arginine at the P.sub.1 position of known pentafluoroethyl-substituted tripeptides, not only is antithrombin activity observed, but an inhibitor highly selective for thrombin versus other proteases, e.g. trypsin is obtained. This new class of compound may provide for a useful alternative or adjunct therapy to already known thrombin inhibitors and is useful in preventing coagulation of stored whole blood and in preventing coagulation in other biological samples for testing or storage.